tbuckley/cabot-search huggingface dataset:
Novel target and treatment agents for natural killer/T-cell lymphoma
Authors: Xiao-Peng Tian, Yi Cao, Jun Cai, Yu-Chen Zhang, Qi-Hua Zou, Jin-Ni Wang, Yu Fang, Jia-Hui Wang, Song-Bin Guo, Qing-Qing Cai
Journal: Journal of Hematology & Oncology (2023)

Abstract The rapidly increasing use of high-throughput screening had produced a plethora of expanding knowledge on the molecular basis of natural killer/T-cell lymphoma (NKTCL), which in turn has revolutionized the treatment. Specifically, the use of asparaginase-containing regimens has led to substantial improvement in survival outcomes in NKTCL patients. Novel treatment strategies that are currently under development include cell-surface-targeted antibodies, immune checkpoint inhibitors, Epstein-Barr virus targeted cytotoxic T lymphocyte, immunomodulatory agents, chimeric antigen receptor T cells, signaling pathway inhibitors and epigenetic targeted agents. In almost all cases, initial clinical studies of newly developed treatment are conducted in patients relapsed, and refractory NKTCL due to very limited treatment options. This review summarizes the results of these novel treatments for NKTCL and discusses their potential for likely use in NKTCL in a wider setting in the future.
IMPemBra: a phase 2 study comparing pembrolizumab with intermittent/short-term dual MAPK pathway inhibition plus pembrolizumab in patients with melanoma harboring the BRAFV600 mutation
Authors: Elisa A Rozeman, Judith M Versluis, Karolina Sikorska, Esmée P Hoefsmit, Petros Dimitriadis, Disha Rao, Ruben Lacroix, Lindsay G Grijpink-Ongering, Marta Lopez-Yurda, Birthe C Heeres, Bart A van de Wiel, Claudie Flohil, Aysegul Sari, Stijn W T P J Heijmink, Daan van den Broek, Annegien Broeks, Jan Willem B de Groot, Marieke A Vollebergh, Sofie Wilgenhof, Johannes V van Thienen, John B A G Haanen, Christian U Blank
Journal: Journal for ImmunoTherapy of Cancer (2023)

Continuous combination of MAPK pathway inhibition (MAPKi) and anti-programmed death-(ligand) 1 (PD-(L)1) showed high response rates, but only limited improvement in progression-free survival (PFS) at the cost of a high frequency of treatment-related adverse events (TRAE) in patients with BRAFV600-mutated melanoma. Short-term MAPKi induces T-cell infiltration in patients and is synergistic with anti-programmed death-1 (PD-1) in a preclinical melanoma mouse model. The aim of this phase 2b trial was to identify an optimal regimen of short-term MAPKi with dabrafenib plus trametinib in combination with pembrolizumab. Patients with treatment-naïve BRAFV600E/K-mutant advanced melanoma started pembrolizumab 200 mg every 3 weeks. In week 6, patients were randomized to continue pembrolizumab only (cohort 1), or to receive, in addition, intermittent dabrafenib 150 mg two times per day plus trametinib 2 mg one time per day for two cycles of 1 week (cohort 2), two cycles of 2 weeks (cohort 3), or continuously for 6 weeks (cohort 4). All cohorts continued pembrolizumab for up to 2 years. Primary endpoints were safety and treatment-adherence. Secondary endpoints were objective response rate (ORR) at week 6, 12, 18 and PFS. Between June 2016 and August 2018, 33 patients with advanced melanoma have been included and 32 were randomized. Grade 3-4 TRAE were observed in 12%, 12%, 50%, and 63% of patients in cohort 1, 2, 3, and 4, respectively. All planned targeted therapy was given in 88%, 63%, and 38% of patients in cohort 2, 3, and 4. ORR at week 6, 12, and 18 were 38%, 63%, and 63% in cohort 1; 25%, 63%, and 75% in cohort 2; 25%, 50%, and 75% in cohort 3; and 0%, 63%, and 50% in cohort 4. After a median follow-up of 43.5 months, median PFS was 10.6 months for pembrolizumab monotherapy and not reached for patients treated with pembrolizumab and intermittent dabrafenib and trametinib (p=0.17). The 2-year and 3-year landmark PFS were both 25% for cohort 1, both 63% for cohort 2, 50% and 38% for cohort 3 and 75% and 60% for cohort 4. The combination of pembrolizumab plus intermittent dabrafenib and trametinib seems more feasible and tolerable than continuous triple therapy. The efficacy is promising and appears to be favorable over pembrolizumab monotherapy. NCT02625337.
The IMPACT framework and implementation for accessible in silico clinical phenotyping in the digital era
Authors: Andrew Wen, Huan He, Sunyang Fu, Sijia Liu, Kurt Miller, Liwei Wang, Kirk E. Roberts, Steven D. Bedrick, William R. Hersh, Hongfang Liu
Journal: npj Digital Medicine (2023)

Abstract Clinical phenotyping is often a foundational requirement for obtaining datasets necessary for the development of digital health applications. Traditionally done via manual abstraction, this task is often a bottleneck in development due to time and cost requirements, therefore raising significant interest in accomplishing this task via in-silico means. Nevertheless, current in-silico phenotyping development tends to be focused on a single phenotyping task resulting in a dearth of reusable tools supporting cross-task generalizable in-silico phenotyping. In addition, in-silico phenotyping remains largely inaccessible for a substantial portion of potentially interested users. Here, we highlight the barriers to the usage of in-silico phenotyping and potential solutions in the form of a framework of several desiderata as observed during our implementation of such tasks. In addition, we introduce an example implementation of said framework as a software application, with a focus on ease of adoption, cross-task reusability, and facilitating the clinical phenotyping algorithm development process.
Decellularized tendon scaffolds loaded with collagen targeted extracellular vesicles from tendon-derived stem cells facilitate tendon regeneration
Authors: Jing Cui, Yan-Jing Zhang, Xuan Li, Jia-Jiao Luo, Lei-Lei Zhao, Xin-Yue Xie, Wei Ding, Jing-Cong Luo, Ting-Wu Qin
Journal: Journal of Controlled Release (2023)
IgA antibody immunotherapy targeting GD2 is effective in preclinical neuroblastoma models
Authors: Marjolein C Stip, Mitchell Evers, Maaike Nederend, Chilam Chan, Karli R Reiding, Mirjam J Damen, Albert J R Heck, Sofia Koustoulidou, Ruud Ramakers, Gerard C Krijger, Remmert de Roos, Edouard Souteyrand, Annelisa M Cornel, Miranda P Dierselhuis, Marco Jansen, Mark de Boer, Thomas Valerius, Geert van Tetering, Jeanette H W Leusen, Friederike Meyer-Wentrup
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Immunotherapy targeting GD2 is very effective against high-risk neuroblastoma, though administration of anti-GD2 antibodies induces severe and dose-limiting neuropathic pain by binding GD2-expressing sensory neurons. Previously, the IgG1 ch14.18 (dinutuximab) antibody was reformatted into the IgA1 isotype, which abolishes neuropathic pain and induces efficient neutrophil-mediated antibody-dependent cellular cytotoxicity (ADCC) via activation of the Fc alpha receptor (FcαRI/CD89). Methods To generate an antibody suitable for clinical application, we engineered an IgA molecule (named IgA3.0 ch14.18) with increased stability, mutated glycosylation sites and substituted free (reactive) cysteines. The following mutations were introduced: N45.2G and P124R (CH1 domain), C92S, N120T, I121L and T122S (CH2 domain) and a deletion of the tail piece P131-Y148 (CH3 domain). IgA3.0 ch14.18 was evaluated in binding assays and in ADCC and antibody-dependent cellular phagocytosis (ADCP) assays with human, neuroblastoma patient and non-human primate effector cells. We performed mass spectrometry analysis of N -glycans and evaluated the impact of altered glycosylation in IgA3.0 ch14.18 on antibody half-life by performing pharmacokinetic (PK) studies in mice injected intravenously with 5 mg/kg antibody solution. A dose escalation study was performed to determine in vivo efficacy of IgA3.0 ch14.18 in an intraperitoneal mouse model using 9464D-GD2 neuroblastoma cells as well as in a subcutaneous human xenograft model using IMR32 neuroblastoma cells. Binding assays and PK studies were compared with one-way analysis of variance (ANOVA), ADCC and ADCP assays and in vivo tumor outgrowth with two-way ANOVA followed by Tukey’s post-hoc test. Results ADCC and ADCP assays showed that particularly neutrophils and macrophages from healthy donors, non-human primates and patients with neuroblastoma are able to kill neuroblastoma tumor cells efficiently with IgA3.0 ch14.18. IgA3.0 ch14.18 contains a more favorable glycosylation pattern, corresponding to an increased antibody half-life in mice compared with IgA1 and IgA2. Furthermore, IgA3.0 ch14.18 penetrates neuroblastoma tumors in vivo and halts tumor outgrowth in both 9464D-GD2 and IMR32 long-term tumor models. Conclusions IgA3.0 ch14.18 is a promising new therapy for neuroblastoma, showing (1) increased half-life compared to natural IgA antibodies, (2) increased protein stability enabling effortless production and purification, (3) potent CD89-mediated tumor killing in vitro by healthy subjects and patients with neuroblastoma and (4) antitumor efficacy in long-term mouse neuroblastoma models.
Prognosis of IGLV3-21R110 chronic lymphocytic leukemia after chemotherapy-based treatment in a real-world analysis
Authors: Paul J. Hengeveld, Hendrik Veelken, Cornelis A. M. van Bergen, Edwin Quinten, Mischa Y. L. Vervoordeldonk, Wahija Ismailzada, Rob S. Barendse, Julie M. N. Dubois, Marinus H. J. van Oers, Christian H. Geisler, Arnon P. Kater, Peter E. Westerweel, Anton W. Langerak, Mark-David Levin
Journal: Leukemia (2023)

Distinctive molecular patterns in the clonotypic B-cell receptor (BCR) classify patients with chronic lymphocytic leukemia (CLL) into immunogenetic subsets with consistent clinicobiological profiles [1].Around 15-25% of all CLL patients are characterized by a clonotypic immunoglobulin (IG) light chain rearrangement using IGLV3-21*01/*04, featuring a stereotyped somatic hypermutation (G110R) at the IGLJ-IGLC border site (IGLV3-21 R110 ) [2-4].Patients with IGLV3-21 R110 CLL present more frequently with advanced disease and have short time to first treatment (TTFT) and overall survival (OS) [2].However, the predictive impact of the IGLV3-21 R110 genotype is less clearly understood.In a recent analysis of two randomized trials that evaluated the efficacy of targeted agents, we did not observe differences in the response, minimal residual disease depth or progression-free survival (PFS) of IGLV3-21 R110 patients, compared to all other patients, suggesting that targeted agents mitigate the adverse risk associated with IGLV3-21 R110 CLL [4].In addition, a pooled analysis of trials demonstrated that, irrespective of their IGHV mutational status, patients with subset #2 CLL, which invariably carry an IGLV3-21 R110 IG light chain, have shorter time to next treatment (TTNT) after chemoimmunotherapy-based treatment [5].However, to determine whether all IGLV3-21 R110 CLL patients should, irrespective of IG heavy chain stereotypy, preferentially receive targeted agents, characterization of the predictive impact of the IGLV3-21 R110 genotype in the context of chemotherapy-based treatment is pivotal.Here, we assess the real-world prognosis of patients with IGLV3-21 R110 CLL after first-line chemotherapy-based treatment.Patient samples were obtained from the biobank of the Leiden University Medical Center (n = 140), the Academic Medical Center Amsterdam Biobank for B cell malignancies (n = 25) and the HOVON-68 databank (n = 55), all approved by the respective institutional ethical review boards [6].All patients provided informed consent.The clonotypic IG light chain sequence was determined previously [2,4].All patients provided informed consent and all TTNT was defined as the interval between the first day of index therapy and the first day of a subsequent line of anti-leukemic therapy or Richter's transformation, while OS was defined as the interval between the first day of index therapy and death.Survival analysis was performed using Kaplan-Meier estimation in R. Statistical significance was evaluated using omnibus and pairwise log-rank testing.
Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix
Authors: Marena Trinidad, Xinying Hong, Steven Froelich, Jessica Daiker, James Sacco, Hong Phuc Nguyen, Madelynn Campagna, Dean Suhr, Teryn Suhr, Jonathan H. LeBowitz, Michael H. Gelb, Wyatt T. Clark
Journal: Genome biology (2023)

Abstract Background Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by mutations in the arylsulfatase A gene ( ARSA ) and categorized into three subtypes according to age of onset. The functional effect of most ARSA mutants remains unknown; better understanding of the genotype–phenotype relationship is required to support newborn screening (NBS) and guide treatment. Results We collected a patient data set from the literature that relates disease severity to ARSA genotype in 489 individuals with MLD. Patient-based data were used to develop a phenotype matrix that predicts MLD phenotype given ARSA alleles in a patient’s genotype with 76% accuracy. We then employed a high-throughput enzyme activity assay using mass spectrometry to explore the function of ARSA variants from the curated patient data set and the Genome Aggregation Database (gnomAD). We observed evidence that 36% of variants of unknown significance (VUS) in ARSA may be pathogenic. By classifying functional effects for 251 VUS from gnomAD, we reduced the incidence of genotypes of unknown significance (GUS) by over 98.5% in the overall population. Conclusions These results provide an additional tool for clinicians to anticipate the disease course in MLD patients, identifying individuals at high risk of severe disease to support treatment access. Our results suggest that more than 1 in 3 VUS in ARSA may be pathogenic. We show that combining genetic and biochemical information increases diagnostic yield. Our strategy may apply to other recessive diseases, providing a tool to address the challenge of interpreting VUS within genotype–phenotype relationships and NBS.
In Response: Taichiro Goto “Kit Use May Not Be Key To Improved Prognosis”; Response to “Akinbobola O, Ray MA, Fehnel C, et al. Institution-Level Evolution of Lung Cancer Resection Quality With Implementation of a Lymph Node Specimen Collection Kit”
Authors: Olawale Akinbobola, Meredith A. Ray, Matthew P. Smeltzer, Raymond U. Osarogiagbon
Journal: Journal of Thoracic Oncology (2023)
Soluble Nogo-Receptor-Fc decoy (AXER-204) in patients with chronic cervical spinal cord injury in the USA: a first-in-human and randomised clinical trial
Authors: George Maynard, Ramakrishnan Kannan, Jian Liu, Weiwei Wang, Tu Kiet T Lam, Xingxing Wang, Crista Adamson, Craig Hackett, Jan M Schwab, Charles Liu, Donald P Leslie, David Chen, Ralph Marino, Ross Zafonte, Adam Flanders, Gilbert Block, Erika Smith, Stephen M Strittmatter
Journal: The Lancet Neurology (2023)
Cognitive outcomes at age 3 years in children with fetal exposure to antiseizure medications (MONEAD study) in the USA: a prospective, observational cohort study
Authors: Kimford J Meador, Morris J Cohen, David W Loring, Abigail G Matthews, Carrie Brown, Chelsea P Robalino, Angela K Birnbaum, Paula E Voinescu, Laura A Kalayjian, Elizabeth E Gerard, Evan R Gedzelman, Julie Hanna, Jennifer Cavitt, Maria Sam, Jacqueline A French, Sean Hwang, Alison M Pack, Page B Pennell
Journal: The Lancet Neurology (2023)
Differential diagnosis of suspected multiple sclerosis: an updated consensus approach
Authors: Andrew J Solomon, Georgina Arrambide, Wallace J Brownlee, Eoin P Flanagan, Maria Pia Amato, Lilyana Amezcua, Brenda L Banwell, Frederik Barkhof, John R Corboy, Jorge Correale, Kazuo Fujihara, Jennifer Graves, Mary Pat Harnegie, Bernhard Hemmer, Jeannette Lechner-Scott, Ruth Ann Marrie, Scott D Newsome, Maria A Rocca, Walter Royal, Emmanuelle L Waubant, Bassem Yamout, Jeffrey A Cohen
Journal: The Lancet Neurology (2023)
Ablation of integrin-mediated cell–collagen communication alleviates fibrosis
Authors: Mugdha Sawant, Fang Wang, Janis Koester, Anja Niehoff, Michele M Nava, Evy Lundgren-Akerlund, Donald Gullberg, Birgit Leitinger, Sara Wickström, Beate Eckes, Thomas Krieg
Journal: Annals of the Rheumatic Diseases (2023)

Activation of fibroblasts is a hallmark of fibrotic processes. Besides cytokines and growth factors, fibroblasts are regulated by the extracellular matrix environment through receptors such as integrins, which transduce biochemical and mechanical signals enabling cells to mount appropriate responses according to biological demands. The aim of this work was to investigate the in vivo role of collagen-fibroblast interactions for regulating fibroblast functions and fibrosis.Triple knockout (tKO) mice with a combined ablation of integrins α1β1, α2β1 and α11β1 were created to address the significance of integrin-mediated cell-collagen communication. Properties of primary dermal fibroblasts lacking collagen-binding integrins were delineated in vitro. Response of the tKO mice skin to bleomycin induced fibrotic challenge was assessed.Triple integrin-deficient mice develop normally, are transiently smaller and reveal mild alterations in mechanoresilience of the skin. Fibroblasts from these mice in culture show defects in cytoskeletal architecture, traction stress generation, matrix production and organisation. Ablation of the three integrins leads to increased levels of discoidin domain receptor 2, an alternative receptor recognising collagens in vivo and in vitro. However, this overexpression fails to compensate adhesion and spreading defects on collagen substrates in vitro. Mice lacking collagen-binding integrins show a severely attenuated fibrotic response with impaired mechanotransduction, reduced collagen production and matrix organisation.The data provide evidence for a crucial role of collagen-binding integrins in fibroblast force generation and differentiation in vitro and for matrix deposition and tissue remodelling in vivo. Targeting fibroblast-collagen interactions might represent a promising therapeutic approach to regulate connective tissue deposition in fibrotic diseases.
Vision Transformers for Computational Histopathology
Authors: Hongming Xu, Qi Xu, Fengyu Cong, Jeonghyun Kang, Chu Han, Zaiyi Liu, Anant Madabhushi, Cheng Lu
Journal: IEEE Reviews in Biomedical Engineering (2023)

Computational histopathology is focused on the automatic analysis of rich phenotypic information contained in gigabyte whole slide images, aiming at providing cancer patients with more accurate diagnosis, prognosis, and treatment recommendations. Nowadays deep learning is the mainstream methodological choice in computational histopathology. Transformer, as the latest technological advance in deep learning, learns feature representations and global dependencies based on self-attention mechanisms, which is increasingly gaining prevalence in this field. This article presents a comprehensive review of state-of-the-art vision transformers that have been explored in histopathological image analysis for classification, segmentation, and survival risk regression applications. We first overview preliminary concepts and components built into vision transformers. Various recent applications including whole slide image classification, histological tissue component segmentation, and survival outcome prediction with tailored transformer architectures are then discussed. We finally discuss key challenges revolving around the use of vision transformers and envisioned future perspectives. We hope that this review could provide an elaborate guideline for readers to explore vision transformers in computational histopathology, such that more advanced techniques assisting in the precise diagnosis and treatment of cancer patients could be developed.
NLRP11 is a pattern recognition receptor for bacterial lipopolysaccharide in the cytosol of human macrophages
Authors: Maricarmen Rojas-Lopez, María Luisa Gil-Marqués, Vritti Kharbanda, Amanda S. Zajac, Kelly A. Miller, Thomas E. Wood, Austin C. Hachey, Keith T. Egger, Marcia B. Goldberg
Journal: Science Immunology (2023)

Endotoxin-bacterial lipopolysaccharide (LPS)-is a driver of lethal infection sepsis through excessive activation of innate immune responses. When delivered to the cytosol of macrophages, cytosolic LPS (cLPS) induces the assembly of an inflammasome that contains caspases-4/5 in humans or caspase-11 in mice. Whereas activation of all other inflammasomes is triggered by sensing of pathogen products by a specific host cytosolic pattern recognition receptor protein, whether pattern recognition receptors for cLPS exist has remained unclear, because caspase-4, caspase-5, and caspase-11 bind and activate LPS directly in vitro. Here, we show that the primate-specific protein NLRP11 is a pattern recognition receptor for cLPS that is required for efficient activation of the caspase-4 inflammasome in human macrophages. In human macrophages, NLRP11 is required for efficient activation of caspase-4 during infection with intracellular Gram-negative bacteria or upon electroporation of LPS. NLRP11 could bind LPS and separately caspase-4, forming a high-molecular weight complex with caspase-4 in HEK293T cells. NLRP11 is present in humans and other primates but absent in mice, likely explaining why it has been overlooked in screens looking for innate immune signaling molecules, most of which have been carried out in mice. Our results demonstrate that NLRP11 is a component of the caspase-4 inflammasome activation pathway in human macrophages.
Therapist-assisted online psychological therapies differing in trauma focus for post-traumatic stress disorder (STOP-PTSD): a UK-based, single-blind, randomised controlled trial
Authors: Anke Ehlers, Jennifer Wild, Emma Warnock-Parkes, Nick Grey, Hannah Murray, Alice Kerr, Alexander Rozental, Graham Thew, Magdalena Janecka, Esther T Beierl, Apostolos Tsiachristas, Rafael Perera-Salazar, Gerhard Andersson, David M Clark
Journal: The Lancet Psychiatry (2023)

Many patients are currently unable to access psychological treatments for post-traumatic stress disorder (PTSD), and it is unclear which types of therapist-assisted internet-based treatments work best. We aimed to investigate whether a novel internet-delivered cognitive therapy for PTSD (iCT-PTSD), which implements all procedures of a first-line, trauma-focused intervention recommended by the UK National Institute for Health and Care Excellence (NICE) for PTSD, is superior to internet-delivered stress management therapy for PTSD (iStress-PTSD), a comprehensive cognitive behavioural treatment programme focusing on a wide range of coping skills.
Safety and efficacy of venglustat in GBA1-associated Parkinson's disease: an international, multicentre, double-blind, randomised, placebo-controlled, phase 2 trial
Authors: Nir Giladi, Roy N Alcalay, Gary Cutter, Thomas Gasser, Tanya Gurevich, Günter U Höglinger, Kenneth Marek, Claudio Pacchetti, Anthony H V Schapira, Clemens R Scherzer, Tanya Simuni, Pascal Minini, S Pablo Sardi, M Judith Peterschmitt
Journal: The Lancet Neurology (2023)
Re: Peter Ka-Fung Chiu, Veeru Kasivisvanathan, Giorgio Gandaglia, European Association of Urology Young Academic Urologists Prostate Cancer Working Party. Moving the Needle: Antibiotic Prophylaxis Is No Longer Required in the Era of Transperineal Prostate Biopsy. Eur Urol. 2023;84:154–55
Authors: Peter Mærhe Lauritzen, Maciej Jacewitz, Eduard Baco, Erik Rud
Journal: European Urology (2023)